Processes for preparing anhydrous and hydrate forms of antihistaminic piperidine derivatives, polymorphs and pseudomorphs thereof

ABSTRACT

The present invention is related to novel processes for preparing anhydrous and hydrated forms of piperidine derivatives, polymorphs and pseudomorphs thereof of the formulas  
                 
 
     which are useful as antihistamines, antiallergic agents and bronchodilators.

[0001] This is a Continuation-In-Part application of patent applicationSer. No. 08/245,731, filed May 18, 1994.

[0002] The present invention is related to novel processes for preparinganhydrous and hydrated forms of piperidine derivatives, polymorphs andpseudomorphs thereof which are useful as antihistamines, antiallergicagents and bronchodilators [U.S. Pat. No. 4,254,129, Mar. 3, 1981, U.S.Pat. No. 4,254,130, Mar. 3, 1981 and U.S. Pat. No. 4,285,958, Apr. 25,1981].

SUMMARY OF THE INVENTION

[0003] The present invention provides a process for preparing anhydrous,pharmaceutically acceptable acid addition salts of piperidinederivatives of the formulas

[0004] wherein

[0005] R₁ represents hydrogen or hydroxy;

[0006] R₂ represents hydrogen; or

[0007] R₁ and R₂ taken together form a second bond between the

[0008] carbon atoms bearing R₁ and R₂;

[0009] n is an integer of from 1 to 5;

[0010] R₃ is —CH₂OH, —COOH or —COOalkyl wherein the alkyl moiety hasfrom 1 to 6 carbon atoms and is straight or branched;

[0011] each of A is hydrogen or hydroxy; and

[0012] pharmaceutically acceptable salts and individual optical isomersthereof,

[0013] comprising subjecting the corresponding hydrated,pharmaceutically acceptable acid addition salt to an azeotropicdistillation.

[0014] In addition, the present invention also provides a process forpreparing anhydrous, pharmaceutically acceptable acid addition salts ofpiperidine derivatives of the formula

[0015] wherein

[0016] R₁ represents hydrogen or hydroxy;

[0017] R₂ represents hydrogen; or

[0018] R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0019] n is an integer of from 1 to 5;

[0020] R₃ is —CH₂OH, —COOH or —COOalkyl wherein the alkyl moiety hasfrom 1 to 6 carbon atoms and is straight or branched;

[0021] each of A is hydrogen or hydroxy; and

[0022] pharmaceutically acceptable salts and individual optical isomersthereof,

[0023] comprising subjecting the corresponding hydrated,pharmaceutically acceptable acid addition salt to a water-minimizingrecrystallization.

[0024] In addition, the present invention provides a process forpreparing the hydrated, pharmaceutically acceptable acid addition saltsof piperidine derivatives of the formula

[0025] wherein

[0026] R₁ represents hydrogen or hydroxy;

[0027] R₂ represents hydrogen; or

[0028] R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0029] n is an integer of from 1 to 5;

[0030] R₃ is —CH₂OH, —COOH or —COOalkyl wherein the alkyl moiety hasfrom 1 to 6 carbon atoms and is straight or branched;

[0031] each of A is hydrogen or hydroxy; and

[0032] pharmaceutically acceptable salts and individual optical isomersthereof,

[0033] comprising subjecting the corresponding anhydrous,pharmaceutically acceptable acid addition salts to an aqueousrecrystallization.

[0034] In addition, the present invention provides processes forpreparing polymorphs of anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride designated herein as Form I and Form III andprocesses for preparing psuedomorphs of hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride designated herein as Form II and Form IV.

[0035] The Form I polymorph may be identified by the followingcharacteristics: a visual melting point (capillary tube) in the range ofabout 196-201° C.; a melt endotherm with extrapolated onset in the rangeof about 195-199° C. as determined by differential scanning calorimetry;and an X-ray powder diffraction pattern essentially as shown in Table 1wherein the XRPD patterns were measured using a powder diffractometerequipped with a Co X-ray tube source. The sample was illuminated with CoKα_(l) radiation and XRPD data were collected from 5 to 55° 2⊖.(intensities may vary radically due to preferred orientation). TABLE 1D-Space, Angstroms Intensity, I/I_(O), % 11.8 30 7.3 30 6.3 65 5.9 355.0 45 4.8 100 4.4 45 3.9 60 3.8 75 3.7 30

[0036] The Form III polymorph may be identified by the followingcharacteristics: a visual melting point (capillary tube) in the range ofabout 166-171° C.; a broad endotherm below about 90° C., a meltendotherm with an extrapolated onset of about 166° C. as determined bydifferential scanning calorimetry; and an X-ray powder diffractionpattern essentially as shown in Table 2 wherein the XRPD patterns weremeasured using a powder diffractometer equipped with a Co X-ray tubesource. The sample was illuminated with Co Kα_(l) radiation and XRPDdata were collected from 5 to 55° 2⊖. (intensities may vary radicallydue to preferred orientation). TABLE 2 D-Space, Angstroms Intensity,I/I_(O), % 9.0 95 4.9 100 4.8 35 4.6 25 4.5 25 3.7 25

[0037] The Form II pseudomorph may be identified by the followingcharacteristics: a visual melting point (capillary tube) in the range ofabout 100-105° C.; a large broad endotherm below about 100° C. and asmall endothermic peak (about 2 joules/gram) with extrapolated onsets inthe range of about 124-126° C. as determined by differential scanningcalorimetry; and an X-ray powder diffraction pattern essentially asshown in Table 3 wherein the XRPD patterns were measured using a powderdiffractometer equipped with a Co X-ray tube source. The sample wasilluminated with Co Kα_(l) radiation and XRPD data were collected from 5to 55° 2⊖. (intensities may vary radically due to preferredorientation). TABLE 3 D-Space, Angstroms Intensity, I/I_(O), % 7.8 456.4 44 5.2 85 4.9 60 4.7 80 4.4 55 4.2 50 4.1 60 3.7 75 3.6 60 3.5 50

[0038] The Form IV pseudomorph may be identified by the followingcharacteristics: a visual melting point (capillary tube) in the range ofabout 113-118° C.; two broad overlapping endotherms below about 100° C.and an additional endotherm with an extrapolated onset at approximately146° C. as determined by differential scanning calorimetry and an X-raypowder diffraction pattern essentially as shown in Table 4 wherein theXRPD patterns were measured using a powder diffractometer equipped witha Co X-ray tube source. The sample was illuminated with Co Kα_(l)radiation and XRPD data were collected from 5 to 55° 2⊖. (intensitiesmay vary radically due to preferred orientation). TABLE 4 D-Space,Angstroms Intensity, I/I_(O), % 10.4 60 7.0 45 6.4 50 5.3 100 5.2 55 4.375 4.1 50 4.0 45 3.8 60 3.5 55

DETAILED DESCRIPTION OF THE INVENTION

[0039] Pharmaceutically acceptable acid addition salts of the compoundsof formula (I) and (II), both anhydrous and hydrated, are those of anysuitable inorganic or organic acid. Suitable inorganic acids are, forexample, hydrochloric, hydrobromic, sulfuric, and phosphoric acids.Suitable organic acids include carboxylic acids, such as, acetic,propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic,tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, anddihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic,4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic,2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic acid, sulfonic acids,such as, methanesulfonic, ethanesulfonic and β-hydroxyethanesulfonicacid.

[0040] As used herein, the term “hydrate” refers to a combination ofwater with a compound of formula (I) or (II) wherein the water retainsits molecular state as water and is either absorbed, adsorbed orcontained within a crystal lattice of the substrate molecule of formula(I) or (II).

[0041] As used herein, the term “adsorped” refers to the physical statewherein the water molecule in the hydrated, pharmaceutically acceptableacid addition salts of piperidine derivatives of the formula (I) and(II) is distributed over the surface of the solid hydrated,pharmaceutically acceptable acid addition salts of piperidinederivatives of the formula (I) and (II).

[0042] As used herein, the term “absorbed” refers to the physical statewherein the water molecule in the hydrated, pharmaceutically acceptableacid addition salts of piperidine derivatives of the formula (I) and(II) is distributed throughout the body of the solid hydrated,pharmaceutically acceptable acid addition salts of piperidinederivatives of the formula (I) and (II).

[0043] Hydrated, pharmaceutically acceptable acid addition salts of thecompounds of formula (I) and (II) are those hydrates ranging fromessentially 0.10 to 5 molecules of water per molecule of substrate saltof formula (I) or (II).

[0044] As used herein, the term “azeotropic mixture” refers to a liquidmixture of two or more substances which behaves like a single substancein that the vapor produced by partial evaporation of liquid has the samecomposition as the liquid. The constant boiling mixture exhibits eithera maximum or minimum boiling point as compared with that of othermixtures of the same substance.

[0045] As used herein, the term “azeotropic distillation” refers to atype of distillation in which a substance is added to the mixture to beseparated in order to form an azeotropic mixture with one or more of theconstituents of the original mixture. The azeotrope or azeotropes thusformed will have boiling points different from the boiling points of theoriginal mixture. As used herein, the term “azeotropic distillation”also refers to co-distillation.

[0046] As used herein, the term “water-minimizing recrystallization”refers to a recrystallization wherein the ratio of anhydrous solvent tosubstrate hydrate is such that the percentage of water present isminimized, thereby inducing precipitation of the anhydrous form of thesubstrate.

[0047] As used herein, the term “aqueous recrystallization” refers tothose processes wherein either 1) a solid material is dissolved in avolume of water or a water/organic solvent mixture sufficient to causedissolution and the solid material recovered by evaporation of thesolvent; 2) a solid material is treated with a minimal amount of wateror a water/organic solvent mixture which is not sufficient to causedissolution, heated to obtain dissolution and cooled to inducecrystallization or 3) a solid material is dissolved in a volume of wateror a water/organic solvent mixture sufficient to cause dissolution andthen the solvent is partially evaporated to form a saturated solutionwhich induces crystallization.

[0048] As used herein, the term “crystal digestion” refers to thatprocess wherein a solid material is treated with a minimal amount ofwater or water/organic solvent mixture which is not sufficient to causedissolution and either heating or stirring at ambient temperature untilthe desired transformation has taken place.

[0049] As used herein, the term “antisolvent” refers to a poor solventfor the substance in question which when added to a solution of thesubstance, causes the substance to precipitate.

[0050] As used herein, the term “suitable temperature” refers to thattemperature which is sufficient to cause dissolution and to permit theprecipitation of the desired substance either upon addition of anantisolvent or upon removal of the co-solvent by azeotropicdistillation.

[0051] The anhydrous, pharmaceutically acceptable acid addition salts ofpiperidine derivatives of the formula (I) and (II) may be prepared fromthe corresponding hydrated, pharmaceutically acceptable acid additionsalts of piperidine derivatives of the formula (I) and (II) bysubjecting the corresponding hydrated, pharmaceutically acceptable acidaddition salts of piperidine derivatives of the formula (I) and (II) toan azeotropic distillation.

[0052] For example, the appropriate hydrated, pharmaceuticallyacceptable acid addition salt of piperidine derivatives of the formula(I) and (II) is first dissolved in a volume of a suitable solvent orsolvent mixture which is sufficient to cause dissolution. Examples ofsuch solvents are water, C₁-C₅ alkanols such as methanol, ethanol andthe like; ketone solvents such as acetone, methyl ethyl ketone and thelike; aliphatic ester solvents such as ethyl acetate, methyl acetate,methyl formate, ethyl formate, isopropyl acetate and the like andaqueous mixtures of these solvents, such as acetone/water, methyl ethylketone/water, water/acetone and water/acetone/ethyl acetate. Anadditional volume of the same solvent used to effect dissolution orsecond suitable anhydrous antisolvent is then added to this solution,which is then heated to a boiling point which is suitable toazeotropically remove water and other low boiling components. Suitableanhydrous antisolvents for use in the azeotropic distillation are, forexample, ketone solvents such as acetone, methyl ethyl ketone and thelike; aliphatic ester solvents such as ethyl acetate, methyl acetate,methyl formate, ethyl formate, isopropyl acetate and the like; C₅-C₈aliphatic solvents such as pentane, hexane and the like; aliphaticnitrites, such as acetonitrile and mixtures of these solvents such asacetone/ethyl acetate and the like. The azeotropic mixture of water andsolvent is removed by distillation until the temperature changes,indicating that the azeotropic mixture is completely removed. Thereaction mixture is cooled and the corresponding anhydrous,pharmaceutically acceptable acid addition salts of piperidinederivatives of the formula (I) and (II) is recovered from the reactionzone by, for example filtration.

[0053] In addition, the anhydrous, pharmaceutically acceptable acidaddition salts of piperidine derivatives of the formula (I) and (II) maybe prepared from the corresponding hydrated, pharmaceutically acceptableacid addition salts of piperidine derivatives of the formula (I) and(II) by subjecting the corresponding hydrated, pharmaceuticallyacceptable acid addition salts of piperidine derivatives of the formula(I) and (II) to a water-minimizing recrystallization.

[0054] For example, the appropriate hydrated, pharmaceuticallyacceptable acid addition salt of piperidine derivatives of the formula(I) and (II) is dissolved in a volume of a suitable anhydrous solvent orsolvent mixture which is sufficient to cause dissolution and heated toreflux. Examples of such solvents are water, C₁-C₅ alkanols such asmethanol, ethanol and the like; ketone solvents such as acetone, methylethyl ketone and the like; aliphatic ester solvents such as ethylacetate, methyl acetate, methyl formate, ethyl formate, isopropylacetate and the like and aqueous mixtures of these solvents, such asacetone/water, methyl ethyl ketone/water, water/acetone andwater/acetone/ethyl acetate. An additional volume of the same solventused to effect dissolution or second suitable anhydrous antisolvent isthen added in a quantity sufficient to initiate precipitation of theanhydrous, pharmaceutically acceptable acid addition salt of piperidinederivatives of the formula (I) and (II). Suitable anhydrous antisolventsare, for example, ketone solvents such as acetone, methyl ethyl ketoneand the like;

[0055] aliphatic ester solvents such as ethyl acetate, methyl acetate,methyl formate, ethyl formate, isopropyl acetate and the like; mixturesof ketone solvents and aliphatic ester solvents such as acetone/ethylacetate and the like;

[0056] C₅-C₈ aliphatic solvents such as pentane, hexane and the like;aliphatic nitriles, such as acetonitrile and mixtures of these solventssuch as acetone/ethyl acetate and the like as well as mixtures of waterand ketone solvents such as acetone/water and the like; and mixtures ofwater, ketone solvents and aliphatic ester solvents such asacetone/water/ethyl acetate. The reaction mixture is cooled and thecorresponding anhydrous, pharmaceutically acceptable acid addItion saltof piperidine derivatives of the formula (I) and (II) is recovered fromthe reaction zone by, for example filtration.

[0057] Polymorphic forms of anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Forms I and III) may be prepared by a variety ofmethods as detailed below. Form III to Form I For example, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) may be prepared from anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form III), by subjecting the anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form III) to a crystal digestion as described above.

[0058] Form II to Form III

[0059] In addition, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form III) may be prepared from hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II), by subjecting the hydrated4-[4-[4(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) to water-minimizing recrystallization asdescribed above.

[0060] Form II to Form I

[0061] In addition, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) may be prepared from hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II), by subjecting the hydrated4-[4-[4(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) to water-minimizing recrystallization asdescribed above or by subjecting the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) to an azeotropic distillation.

[0062] Form IV to Form I

[0063] In addition, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) may be prepared from hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV), by subjecting the hydrated4-[4-[4(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV) to water-minimizing recrystallization or toan azeotropic distillation as described above.

[0064] The hydrated, pharmaceutically acceptable acid addition salts ofpiperidine derivatives of the formula (I) may be prepared from thecorresponding compound of the formula (II) wherein R₃ is —COOalkyl bysubjecting the corresponding compound of the formula (II) wherein R₃ is—COOalkyl to a reduction using an appropriate reducing agent, such assodium borohyride, potassium borohydride, sodium cyanoborohydride, ortetramethylammonium borohydride in a suitable solvent, such as,methanol, ethanol, isopropyl alcohol or n-butanol, aqeuous mixturesthereof or basic solutions thereof, at temperatures ranging from about0° C. to the reflux temperature of the solvent, and the reaction timevaries from about ½ hour to 8 hours. After quenching and acidifying withan suitable acid, such as hydrochloric acid, the hydrated,pharmaceutically acceptable acid addition salts of piperidinederivatives of the formula (I) are recovered from the reaction zone bycrystallization and filtration.

[0065] In addition, the hydrated, pharmaceutically acceptable acidaddition salts of piperidine derivatives of the formula (I) and (II) maybe prepared from the corresponding anhydrous, pharmaceuticallyacceptable acid addition salts of the formula (I) and (II) by subjectingthe corresponding anhydrous, pharmaceutically acceptable acid additionsalts of formula (I) and (II) to an aqueous recrystallization.

[0066] For example, the appropriate anhydrous, pharmaceuticallyacceptable acid addition salt of piperidine derivatives of the formula(I) and (II) is treated with a minimal volume of water or suitablewater/organic solvent mixture which is insufficient to cause dissolutionand heated to reflux. The reaction mixture is cooled and thecorresponding hydrated, pharmaceutically acceptable acid addition saltof piperidine derivatives of the formula (I) and (II) is recovered fromthe reaction zone by, for example filtration. Alternatively, theappropriate anhydrous, pharmaceutically acceptable acid addition salt ofpiperidine derivatives of the formula (I) and (II) is treated with avolume of water or a suitable water/organic solvent mixture which issufficient to cause dissolution and the water or water/organic solventis partially or completely evaporated to a volume which inducescrystallization of the hydrated, pharmaceutically acceptable acidaddition salts of piperidine derivatives of the formula (I) and (II).Suitable solvents for use in the above recrystallization are water,acetone/water, ethanol/water, methyl ethyl ketone/aqueous methanol,methyl ethyl ketone/water and the like.

[0067] The pseudomorphic forms of hydrated4-[4-[4(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Forms II and IV) may be prepared by a variety ofmethods as detailed below. Ethyl Ester/Ketone to Form II Hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV) may be prepared from ethyl4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride or free base as described above for the generalpreparation of the hydrated, pharmaceutically acceptable acid additionsalts of piperidine derivatives of the formula (I) from thecorresponding compound of the formula (II) wherein R₃ is —COOalkyl, butrapdily adding water over a period of time ranging from 1 minute to 45minutes at a temperature range of about −20° C. to 50° C. to precipitatethe hydrated4-[4-[4(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II).

[0068] Ethyl Ester/Ketone to Form IV

[0069] Hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV) may be prepared from ethyl4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride or free base as described above for the generalpreparation of the hydrated, pharmaceutically acceptable acid additionsalts of piperidine derivatives of the formula (I) from thecorresponding compound of the formula (II) wherein R₃ is —COOalkyl, butslowly adding water over a period of time ranging from about 30 minutesto 24 hours and at a temperature range of about 0° C. to 50° C.,optionally with seeding, to precipitate the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV).

[0070] Form I to Form II

[0071] Hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) may be prepared from anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) by subjecting hydrated4-[4-[4(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) to an aqueous recrystallization as definedabove.

[0072] Starting materials for use in the present invention are readilyavailable to one of ordinary skill in the art. For example, ethyl4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride is described in U.S. Pat. No. 4,254,129, Mar. 3, 1981.

[0073] The following examples present typical processes for preparingthe anhydrous and hydrated, pharmaceutically acceptable acid additionsalts of piperidine derivatives of the formula (I) and (II), polymorphsand pseudomorphs therof. These examples are understood to beillustrative only and are not intended to limit the scope of the presentinvention in any way. As used herein, the following terms have theindicated meanings: “g” refers to grams; “mol” refers to mole; “mmol”refers to millimoles; “mL” refers to milliliters; “bp” refers to boilingpoint; “mp” refers to melting point; “° C.” refers to degrees Celsius;“mm Hg” refers to millimeters of mercury; “uL” refers to microliters;“Ugg” refers to micrograms; and “μM” refers to micromolar.

[0074] Differential Scanning Calorimetry analysis were performed using aTA 2910 DSC with open aluminum pans. The samples were heated to 240° C.at 5° C./minute with a 50 mL/minute nitrogen purge.

[0075] X-Ray Powder Diffraction analyses were performed as follows:

[0076] The samples were loaded into a quartz (zero scatter) sampleholder for the XRPD pattern measurement. The XRPD patterns were measuredusing a powder diffractometer equipped with a Co X-ray tube source,primary beam monochromator, and position sensitive detector (PSD). Theincident beam was collimated using a 10 divergence slit. The active areaon the PSD subtended approximately 5° 2⊖. The source was operated at 35kV and 30 mA and the sample was illuminated with Co Kα_(l) radiation.XRPD data were collected from 5 to 55° 2⊖at a rate of 0.25° 2⊖/minuteand a step width of 0.02° 2⊖. The XRPD patterns were measured withoutthe addition of an internal calibrant. Peak positions and intensitiesfor the most prominent features were measured using a double-derivativepeak picking method. X-ray peaks with I/I_(o) greater than 20% werereported. The cutoff was chosen arbitrarily. The intensities are roundedto the nearest 5%. Certain peaks appear sensitive to preferredorientation that is caused by changes in crystallite morphology. Thisresults in large changes in the I/Io value.

EXAMPLE 1 Preparation of Form II

[0077]4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride

[0078] Method A

[0079] Mix ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride (101.92 g, 0.1807 mol) and methanol (510 mL) and stir.Rapidly add 50% sodium hydroxide (72.27 g, 0.903 mol) and wash in withwater (61 mL). Heat to reflux for 2 hours, allow to cool to 35° C. andtreat with sodium borohydride (3.42 g, 0.0903 mol). Add water (100 mL)and maintain at 35° C. for 10 hours. Add 37% hydrochloric acid (53.0 g)to adjust pH to 11.5. Add acetone (26.5 mL) and water (102 mL). Hold at35° C. for 2 hours and adjust to pH 2.5 with 37% hydrochloric acid(44.69 g). Dilute with water (408 mL), cool to −15° C., stir for 1.5hours and collect the precipitate by vacuum filtration. Wash thefiltercake with deionized water (3×100 mL) and vacuum dry to give4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (97.10 g).

[0080] Method B

[0081] Place ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride (60.01 g, 0.106 mol) in a 1-L three necked round-bottomflask and fit the flask with a mechanical stirrer, a Claisen head, athermometer and a reflux condenser with a nitrogen bubbler on top. Addmethanol (300 mL) and turn the stirrer on. Dilute the slurry with water(60 mL) and heat to 52-54° C. over 15-20 minutes. Hold at 52° C. for 2hours and then add 50% sodium hydroxide (42.54 g, 0.532 mol). Heat at73° C. for approximately 1 hour, 45 minutes, cool to less than 35° C.using a water bath and then add sodium borohydride (2.02 g, 0.0534 mol).Stir overnight at 35° C., treat with acetone (15.5 mL) and stir for 2hours at 35° C. Acidify the mixture to a pH of 1.85 with 28%hydrochloric acid (75.72 g), dilute with water (282 mL), stir for about30 minutes and cool over about 2 hours to −15° C. Filter the solids offand wash with water (2×75 mL) and ethyl acetate (2×75 mL). Vacuum drythe solid and allow to stand for 2 days to give4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (57.97 g, 91.5%) as a fine powder.

[0082] Method C

[0083] Place ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate(56.12 g, 0.1064 mol) in a 1-L three necked round-bottom flask and fitthe flask with a mechanical stirrer, a Claisen head, a thermometer and areflux condenser with a nitrogen bubbler on top. Add methanol (300 mL)and turn the stirrer on. Dilute the slurry with water (60 mL) and heatto reflux using a heating mantle controlled by a Therm-O-Watch. When themixture reaches about 35° C., treat with 50% sodium hydroxide (34.05 g,0.4256 mol) and rinse in with water (42 mL). Stir at reflux for 2 hours,15 minutes, cool over 1 hour to 35° C. and then treat with sodiumborohydride (2.02 g, 0.0534 mol). Stir for 7.5 hours and allow to standat room temperature without stirring for 1.75 days. Warm the mixture to35° C. and quench with acetone (15.5 mL, 0.21 mol) and stir for 2 hours.Add water (60 mL) and adjust the pH to 2.5 with 32% hydrochloric acid(65.22 g). Cool to 40° C. and rinse the pH probe with water (25 mL). Addwater over about 30 minutes (192 mL), hold the temperature at 33° C. for10 minutes and add a few seed crystals. Cool the slurry to −12° C. overabout 45minutes and isolate the solid by filtration (586.2 g). Wash withwater (2×100 mL) and then with ethyl acetate (100 mL, prechilled toabout −10° C.). Vacuum dry overnight (1 mm g, 50° C.) to give4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (58.86 g, 98%) as a white solid.

EXAMPLE 2 Preparation of Form IV

[0084]4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride

[0085] (Form IV)

[0086] Place ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate(56.12 g, 0.1064 mol) in a 1-L three necked round-bottom flask and fitthe flask with a mechanical stirrer, a Claisen head, a thermometer and areflux condenser with a nitrogen bubbler on top. Add methanol (300 mL)and turn the stirrer on. Dilute the slurry with water (60 mL) and heatto reflux using a heating mantle controlled by a Therm-O-Watch. When themixture reaches about 35° C., treat with 50% sodium hydroxide (34.05 g,0.4256 mol) and rinse in with water (42 mL). Stir at reflux for 2 hours,15 minutes, cool over 1 hour to 35° C. and then treat with sodiumborohydride (2.02 g, 0.0534 mol). Stir for 7.5 hours and allow to standat room temperature without stirring for 1.75 days. Warm the mixture to35° C. and quench with acetone (15.5 mL, 0.21 mol) and stir for 2 hours.Add water (60 mL) and adjust the pH to 2.5 with 32% hydrochloric acid(65.22 g). Cool to 40° C. and rinse the pH probe with water (25 mL).Hold the temperature at 33° C. for 10 minutes, add a few seed crystalsand add water over about 4 hours (192 mL) at 35° C. Cool the slurry to−12° C. over about 45 minutes and isolate the solid by filtration (586.2g). Wash with water (2×100 mL) and then with ethyl acetate (100 mL,prechilled to about −10° C.). Vacuum dry overnight (1 mmHg, 50° C.) togive4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form IV); mp 115-116° C. (dec).

[0087] XRPD: Table 5 reflux. Reflux for 10 minutes, then slowly addadditional ethyl acetate (23 mL over 10 minutes) and reflux for anadditional 15 minutes. Add additional ethyl acetate (60 mL over 5-10minutes) and continue refluxing for 15 minutes. Cool to approximately 8°C. in an ice bath, filter the solid and wash with ethyl acetate (85 mL).Vacuum dry at 55° C. for 1.5 hours to give the title compound (18.16 g,95%).

EXAMPLE 4 Conversion of Form II to Form I

[0088]4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride

[0089] Method A:

[0090] Treat4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (5.00 g, 0.0083 mol) withmethylethyl ketone (130 mL). Slowly add water (0.4 mL), filter throughfilter aid and wash the filter cake with methylethyl ketone (20 mL).Heat to reflux and distill off 75 mL of solvent, cool to −15° C. andcollect by vacuum filtration. Wash with methylethyl ketone (2×10 mL) andvacuum dry at 60° C. to give the title compound (4.33 g, 97%); mp196-198° C.

[0091] Method B:

[0092] Treat4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (1.4 g) with acetone (60 mL) andheat to reflux. Reduce the volume to approximately 35 mL to remove allwater which boils off as an azeotrope (88/12: acetone/water). Cool thesolution and collect the title compound as a crystalline solid.

[0093] Method C:

[0094] Mix4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (53.88 g, 0.lOOmol) and add water(4.79 g) and methyl ethyl ketone (240 mL). Stir until the solid is

[0095] Method B

[0096] Mix water (35.5 mL), methanol (26.3 mL) and sodium chloride (2.59g). Add4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) (4.77 g). Heat to reflux on a steam bathuntil dissolution and cool to −10° C. Filter the resulting solid, washwith water (2×25 mL) and vacuum dry overnight to give the title compound(4.80 g).

EXAMPLE 6 Conversion of Form II into Form III

[0097]4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride

[0098] (Form III)

[0099] Place4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (55.56 g, 0.0929 mol having 10%water) in a pressure bottle along with water (2.96 g) and acetone (38.1g). Seal the bottle tightly and heat to approximately 80° C. Cool toabout 50° C., filter through filter aid in a coarse sintered glassfunnel and dilute with acetone (90 g). Transfer to a 1 L flask fittedwith a mechanical stirrer, thermometer and a reflux condenser. Heat themixture to reflux and allow to cool and stir over the weekend. Cool to−15° C. and filter on a coarse sintered glass funnel, wash with ethylacetate (2×50 mL) and vacuum dry at 50° C.

[0100] Place a majority of the solid obtained (45.24 g) in a 500 mLthree necked flask fitted with a mechanical stirrer, thermometer and areflux condenser. Add acetone (240 mL) and water (4.82 g) and reflux themixture overnight. Allow the slurry to cool to 35° C. and place in anice water bath and cool to less then 5° C. Filter the solid off on acoarse sintered glass funnel, wash with ethyl acetate (50 mL) and vacuumdry at 50 C for several hours to give the title compound as a whitecrystalline powder (43.83 g, 97%); mp 166.5-170.5° C.

[0101] XRPD: Table 7 TABLE 7 D-Space, Angstroms Intensity, I/I_(O), %8.95 95 4.99 20 4.88 100 4.75 35 4.57 25 4.47 25 4.46 20 3.67 20 3.65 25

EXAMPLE 7 Conversion of Form III into Form I

[0102]4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride

[0103] (Form I)

[0104] Place4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form III) (40.0 g as an ethyl acetate wetcake-27.9 gdry basis) in a 1L three necked flask fitted with a mechanical stirrer,thermometer and a reflux condenser. Add acetone (240 mL) and heat themixture to reflux for about 20 hours. Cool the slurry to −15° C. andisolate the solids by filtration on a coarse sintered glass frit funnel.Wash with ethyl acetate (50 mL) and vacuum dry overnight to give thetitle compound (26.1 g, 93.7%); mp 197.5-199.5° C.

[0105] XRPD: Table 8 TABLE 8 D-Space, Angstroms Intensity, I/I_(O), %11.75 35 7.23 35 6.24 60 5.89 40 5.02 20 4.94 30 4.83 100 4.44 30 3.9375 3.83 20 3.77 85 3.71 25 3.62 30 3.32 25 3.31 20

EXAMPLE 8 Conversion of Form IV into Form I

[0106] 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride

[0107] (Form I)

[0108] Place4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form IV) (54.35 g, 0.0970 mol, having 4%water present) in a pressure bottle along with water (4.16 g) andacetone (38.1 g). Seal the bottle tightly and heat to approximately 80°C. Cool to less then 60° C., filter through filter aid in a coarsesintered glass funnel and rinse the filter cake with acetone (32.4 g).Place acetone (215 g) in a 1L three necked flask fitted with amechanical stirrer, thermometer, a reflux condenser and containing asmall amount of Form I crystals and heat to reflux. Add a portion of theacetone/water solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form IV) (47.65 g) to the refluxing acetoneover about 10 minutes. Slowly add ethyl acetate (157.5 g) over 45minutes then add the remaining portion of the acetone/water solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form IV), rinsed in with about 20 mL ofacetone. Add additional ethyl acetate (157.5 g) over 45 minutes to 1hour, maintaining the slurry at reflux. Stir for 15 minutes, cool to−15° C. and vacuum filter the white solid on a 350 mL coarse sinteredglass funnel. Wash the solids with ethyl acetate (2×50 mL) and vacuumdry overnight to give the title compound (50.36 g, 97%); mp 198-199.5°C.

[0109] XRPD: Table 9 TABLE 9 D-Space, Angstroms Intensity, I/I_(O), %14.89 20 11.85 20 7.30 20 6.28 70 5.91 25 5.55 20 5.05 25 4.96 55 4.85100 4.57 45 4.45 55 3.94 45 3.89 20 3.84 20 3.78 60 3.72 35 3.63 20 3.0720 3.04 20 2.45 20

[0110] The polymorphic and pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compounds of this invention are useful asantihistamines, antiallergy agents and bronchodilators and may beadministered alone or with suitable pharmaceutical carriers, and can bein solid or liquid form such as, tablets, capsules, powders, solutions,suspensions or emulsions.

[0111] The polymorphic and pseudomorphic4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compounds of this invention can be administeredorally, parenterally, for example, subcutaneously, intravenously,intramuscularly, intraperitoneally, by intranasal instillation or byapplication to mucous membranes, such as, that of the nose, throat andbronchial tubes, for example, in an aerosol spray containing smallparticles of a compound of this invention in a spray or dry powder form.

[0112] The quantity of polymorphic or pseudomorphic4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compound administered will vary depending on thepatient and the mode of administration and can be any effective amount.The quantity of polymorphic or pseudomorphic4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compound administered may vary over a wide range toprovide in a unit dosage an effective amount of from about 0.01 to 20mg/kg of body weight of the patient per day to achieve the desiredeffect. For example, the desired antihistamine, antiallergy andbronchodilator effects can be obtained by consumption of a unit dosageform such as a tablet containing 1 to 500 mg of a polymorphic orpseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compound of this invention taken 1 to 4 times daily.

[0113] The solid unit dosage forms can be of the conventional type.Thus, the solid form can be a capsule which can be the ordinary gelatintype containing a polymorphic or pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compound of this invention and a carrier, forexample, lubricants and inert fillers such as lactose, sucrose orcornstarch. In another embodiment the polymorphic or pseudomorphic4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compound is tableted with conventional tablet basessuch as lactose, sucrose or cornstarch or gelatin, disintegrating agentssuch as cornstarch, potato starch or alginic acid, and a lubricant suchas stearic acid or magnesium stearate.

[0114] The polymorphic or pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compounds of this invention may also be administeredin injectable dosages by solution or suspension of the compounds in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid such as water and oils, with or without theaddition of a surfactant and other pharmaceutically acceptableadjuvants. Illustrative of oils there can be mentioned those ofpetroleum, animal, vegatable or synthetic origin, for example, peanutoil, soybean oil or mineral oil. In general, water, saline, aqueousdextrose and related sugar solutions and glycols such as propyleneglycol or polyethylene glycol are preferred liquid carriers,particularly for injectable solutions.

[0115] For use as aerosols the compounds of this invention in solutionor suspension may be packaged in a pressurized aerosol containertogether with suitable propellants, for example, hydrocarbon propellantssuch as, propane, butane or isobutane with the usual adjuvants as may beadministered in a non-pressurized form such as in a nebulizer oratomizer.

[0116] The term patient as used herein is taken to mean warm bloodedanimals, birds, mammals, for example, humans, cats, dogs, horses, sheep,bovine cows, pigs, lambs, rats, mice and guinea pigs.

What is claimed is:
 1. A process for preparing a compound of the formula

wherein R₁ represents hydrogen or hydroxy; R₂ represents hydrogen; or R₁and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂; n is an integer of from 1 to 5; R₃ is —CH₂OH, —COOHor —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms andis straight or branched; W is —CH(OH)— or —C(═O)—; A is hydrogen orhydroxy; Y is a pharmaceutically acceptable acid; and the individualoptical isomers thereof, comprising subjecting a compound of the formulaR₃ is —CH₂OH, —COOH or —COOalkyl wherein the alkyl moiety has from 1 to6 carbon atoms and is straight or branched; W is —CH(OH)— or —C(═O)—; Ais hydrogen or hydroxy; Y is a pharmaceutically acceptable acid; and theindividual optical isomers thereof, comprising subjecting a compound ofthe formula

and the individual optical isomers thereof, wherein R₁, R₂, R₃, n, W, Aand Y are defined above and X is a number ranging essentially from 0.10to 5 to a water-minimizing recrystallization.
 3. A process for preparinga compound of the formula

wherein R₁ represents hydrogen or hydroxy; R₂ represents hydrogen; or R₁and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂; n is an integer of from 1 to 5; R₃ is —CH₂OH, —COOHor —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms andis straight or branched; W is —CH(OH)— or —C(═O)—; A is hydrogen orhydroxy; Y is a pharmaceutically acceptable acid; X is a number rangingessentially from 0.1 to 5; and the individual optical isomers thereof,comprising subjecting a compound of the formula

and the individual optical isomers thereof wherein R₁, R₂, R₃, n, A, Wand Y are as defined above, to an aqueous recrystallization.
 4. Aprocess for preparing a compound of the formula

and the individual optical isomers thereof, wherein Y is apharmaceutically acceptable acid, comprising subjecting a compound ofthe formula

wherein Y is as defined above and X is a number ranging essentially from0.10 to 5 to an azeotropic distillation.
 5. A process for preparing acompound of the formula

and the individual optical isomers thereof, wherein Y is apharmaceutically acceptable acid, comprising subjecting a compound ofthe formula

wherein Y is as defined above and X is a number ranging essentially from0.10 to 5 to a water-minimizing recrystallization.
 6. A process forpreparing a compound of the formula

and the individual optical isomers thereof, wherein Y is apharmaceutically acceptable acid and X is a number ranging essentiallyfrom 0.10 to 5, comprising subjecting a compound of the formula

and the individual optical isomers thereof, wherein R₁, R₂, R₃, n, W, Aand Y are defined above and X is a number ranging essentially from 0.10to 5 to an azeotropic distillation.
 2. A process for preparing acompound of the formula

wherein R₁ represents hydrogen or hydroxy; R₂ represents hydrogen; or R₁and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂; n is an integer of from 1 to 5;

wherein Y is as defined above to an aqueous recrystallization.
 7. Aprocess according to claim 4 , claim 5 or claim 6 wherein Y is HCl.
 8. Aprocess according to claim 7 wherein x is a number ranging from 1 to 4.9. A process according to claim 8 wherein x is a number ranging from 2to
 3. 10. A compound of the formula

and the individual optical isomers thereof, formed by the processcomprising the steps of: a) treating a compound of the formula

wherein X is a number ranging from 0.1 to 5 and the individual opticalisomers thereof, with a suitable solvent or solvent mixture; b) heatingthe mixture to a suitable temperature; and c) cooling the mixture tocomplete crystallization.
 11. A compound of the formula

and the individual optical isomers thereof, formed by the processcomprising the steps of: a) treating a compound of the formula

wherein X is a number ranging from 0.1 to 5 and the individual opticalisomers thereof, with a suitable anhydrous solvent or solvent mixture inan amount sufficient to cause dissolution; b) heating the mixture to asuitable temperature. c) adding an additional volume of a suitableanhydrous solvent or solvent mixture in a quantity sufficient toinitiate crystallization; and d) cooling the reaction mixture tocomplete crystallization.
 12. A compound of the formula

wherein X is a number ranging from 0.1 to 5 and the individual opticalisomers thereof, formed by the process comprising the steps of: a)treating a compound of the formula

and the individual optical isomers thereof with a suitable solvent; b)heating the mixture to a suitable temperature; and c) cooling themixture to initiate crystallization.
 13. Form I anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic14. Form II hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride.
 15. Form III anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride.
 16. Form IV hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride.
 17. A pharmaceutical composition comprising aneffective antiallergic amount of a compound of claim 13 in admixture orotherwise in association with an inert carrier.
 18. A pharmaceuticalcomposition comprising an effective antiallergic amount of a compound ofclaim 14 in admixture or otherwise in association with an inert carrier.19. A pharmaceutical composition comprising an effective antiallergicamount of a compound of claim 15 in admixture or otherwise inassociation with an inert carrier.
 20. A pharmaceutical compositioncomprising an effective antiallergic amount of a compound of claim 16 inadmixture or otherwise in association with an inert carrier.
 21. Amethod of treating allergic reactions in a patient in need thereof whichcomprises administering to said patient an anti-allergically effectiveamount of a compound of claim 13 .
 22. A method of treating allergicreactions in a patient in need thereof which comprises administering tosaid patient an anti-allergically effective amount of a compound ofclaim 14 .
 23. A method of treating allergic reactions in a patient inneed thereof which comprises administering to said patient ananti-allergically effective amount of a compound of claim 15 .
 24. Amethod of treating allergic reactions in a patient in need thereof whichcomprises administering to said patient an anti-allergically effectiveamount of a compound of claim 16 .
 25. A process for preparing the FormI anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]α,α-dimethylbenzeneaceticacid hydrochloride which comprises subjecting Form II hydrated4-[4-[4(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride to a water-minimizing recrystallization.
 26. Aprocess according to claim 25 wherein suitable anhydrous solvents orsolvent mixtures which are sufficient to cause dissolution are acetoneand water and a suitable anhydrous antisolvent is ethyl acetate.
 27. Aprocess for preparing the Form I anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride which comprises subjecting Form II hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride to an azeotropic distillation.
 28. A processaccording to claim 27 wherein suitable solvents or solvent mixtureswhich are sufficient to cause dissolution are methanol, acteone/waterand methyl ethyl ketone/water and a suitable anhydrous antisolvent ismethyl ethyl ketone.
 29. A process for preparing the Form I anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride which comprises subjecting Form III anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride to a crystal digestion.
 30. A process for preparingthe Form I anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride which comprises subjecting Form IV hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzenecaceticacid hydrochloride to a water-minimizing recrystallization.
 31. Aprocess according to claim 30 wherein suitable anhydrous solvents orsolvent mixtures which are sufficient to cause dissolution are acetoneand water and a suitable anhydrous antisolvent is ethyl acetate.
 32. Aprocess for preparing the Form I anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride which comprises subjecting Form IV hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride to an azeotropic distillation.
 33. A processaccording to claim 32 wherein suitable solvents or solvent mixtureswhich are sufficient to cause dissolution are methanol, acteone/waterand methyl ethyl ketone/water and a suitable anhydrous antisolvent ismethyl ethyl ketone.
 34. A process for preparing the Form II hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride which comprises: a) reacting ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetatehydrochloride with an appropriate reducing agent in a suitable solvent;b) acidifying with hydrochloric acid; and c) adding water over a periodof time ranging from 1 minute to 45 minutes at a temperature range ofabout −20° C. to 50° C.
 35. A process according to claim 34 wherein thewater is added over a period of time ranging from 10 minutes to 30minutes at a temperature range of about 0° C. to 40° C.
 36. A processaccording to claim 35 wherein the water is added over a period of timeranging from 10 minutes to 30 minutes at a temperature range of about20° C. to 40° C.
 37. A process for preparing the Form II hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride which comprises: a) reacting ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetatewith an appropriate reducing agent in a suitable solvent; b) acidifyingwith hydrochloric acid; and c) adding water over a period of timeranging from 1 minute to 45 minutes at a temperature range of about −20°C. to 50° C.
 38. A process according to claim 37 wherein the water isadded over a period of time ranging from 10 minutes to 30 minutes at atemperature range of about 0° C. to 40° C.
 39. A process according toclaim 38 wherein the water is added over a period of time ranging from10 minutes to 30 minutes at a temperature range of about 20° C. to 40°C.
 40. A process for preparing the Form II hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride which comprises subjecting Form I anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride to an aqueous recrystallization.
 41. A process forpreparing the Form III anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride which comprises subjecting Form II hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride to a water-minimizing recrystallization.
 42. Aprocess for preparing the Form IV hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride which comprises: a) reacting ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetatehydrochloride with an appropriate reducing agent in a suitable solvent;b) acidifying with hydrochloric acid; and c) adding water over a periodof time ranging from 30 minutes to 24 hours at a temperature range ofabout 0° C. to 50° C.
 43. A process according to claim 42 wherein thewater is added over a period of time ranging from 1 hour to 12 hours ata temperature range of about 10° C. to 40° C.
 44. A process according toclaim 43 wherein the water is added over a period of time ranging from 2hours to 8 hours at a temperature range of about 20° C. to 40° C.
 45. Aprocess for preparing the Form IV hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride which comprises: a) reacting ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetatewith an appropriate reducing agent in a suitable solvent; b) acidifyingwith hydrochloric acid; and c) adding water over a period of timeranging from 30 minutes to 24 hours at a temperature range of about 0°C. to 50° C.
 46. A process according to claim 45 wherein the water isadded over a period of time ranging from 1 hour to 12 hours at atemperature range of about 10° C. to 40° C.
 47. A process according toclaim 46 wherein the water is added over a period of time ranging from 2hours to 8 hours at a temperature range of about 20° C. to 40° C.